Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Oxygen consumption by muscle during exercise depends on convective oxygen delivery, diffusion of oxygen from the capillaries to mitochondria and the activation state, oxygen affinity and respiratory capacity of muscle mitochondria. The long-term objective is to understand the relative contributions of the circulatory and muscle oxidative systems in defining muscle oxygen uptake in humans during acute exercise and how these systems are regulated and adapt to physical training. My short-term objectives build upon recent advances integrating components of the oxygen cascade that center on two main themes.

Theme I focuses on the role the central circulation, and the mechanisms regulating regional distribution of blood flow to muscle through the interaction of autonomic nervous system and local muscle vasodilatory mechanisms. This research builds on recent work employing novel methods to quantify blood pumped by the heart, regional limb and muscle microcirculatory blood flow during exercise in humans combined with arterial and venous sampling across an exercising limb.

Theme II examines the components of oxygen diffusion from the capillaries to muscle mitochondria, and how muscle mitochondria are regulated structurally and functionally. This work integrates methods to measure blood flow in the limbs, blood sampling to measure oxygen content, and mitochondrial respiratory function in muscle biopsies.

Aim 1 . The role of the circulation for increasing peak muscle oxygen uptake with training . Exercise training increases muscle mitochondrial volume and muscle oxidative capacity. However, a higher muscle oxygen uptake can be achieved through a greater distribution of blood flow to contracting muscle, a greater density of blood vessels, slowing of the rate of passage of blood cells through the muscle allow greater diffusion of oxygen and a higher relative activation of mitochondria. This research program will quantify the relative roles of the central, regional and microcirculations and muscle oxidative capacity to advance our understanding of adaptive response of the components of the oxygen cascade in humans.

Aim 2 . The role of mitochondria in muscle oxygen extraction during exercise .

It has long been known that training increases muscle oxygen extraction. This research plan will examine how changes in the affinity of mitochondria for oxygen increases muscle oxygen uptake. This program of research will examine how oxygen affinity is regulated acutely by altering the rate at which mitochondria are activated. Also to be examined is whether the form of enzyme expressed in mitochondria that binds oxygen (cytochrome c oxidase) is altered over time with exercise training. Using advanced imaging with electron microscopy, changes in the volume of the inner mitochondrial membrane where most cellular energy is produced will be determined to examine a novel mechanism regulating oxygen uptake.